Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits

Abstract

Aims/hypothesisGestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. MethodsWe collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Womens and Childrens Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. ResultsWe identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42x10-29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2h OGTT glucose levels were four out of four, six out of nine, 10 out of 11 five out of seven and four out of four, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. Conclusions/interpretationOur findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. Data availabilityFull summary statistics of GDM, FPG, OGTT0H, OGTT1H and OGTT2H will be made available in the GVM database and the GWAS Catalog upon publication. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIPrevious genome-wide association studies on gestational diabetes mellitus (GDM) and glycaemic levels in Asian populations have been limited to sample sizes of a few thousand participants. C_LIO_LIThere is a lack of research investigating the potential causal relationships between various pregnancy indicators and GDM as well as glycaemic levels. C_LI What is the key question?O_LIWhat are the genetic and molecular factors that contribute to GDM and glycaemic levels in an under-represented population of Chinese pregnant women in East Asia? C_LI What are the new findings?O_LIFour genetic loci were significantly associated with GDM risk, with MTNR1B being the most prominent. A total of 31 genetic loci, including 14 novel loci, were significantly associated with four commonly measured glycaemic traits. C_LIO_LIA genetically higher lymphocyte percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with increased glucose levels and an elevated risk of GDM. C_LI How might this impact on clinical practice in the foreseeable future?O_LIIndividuals with GDM risk variants could receive special attention during early pregnancy to mitigate the risk of adverse pregnancy outcomes associated with GDM and higher glycaemic levels. Clinical trials may be warranted to examine the potential of interventions such as nutrition therapy or medication for modulating inflammatory responses and reducing GDM incidence. C_LI